Hypoxia inducible factor (HIF)-1? is a transcription factor that has been shown to be up-regulated in almost all types of chronic kidney diseases (CKD). HIF-1? stimulates the collagen accumulation by activating fibrogenic factors. There is evidence suggesting that the long-term activation of HIF-1? is injurious in CKD, although upregulation of HIF-1? is protective in acute kidney injury. The coexistent hypertension plays a predominant role in the progression of CKD. Despite the findings that impaired renal autoregulation transmits the elevated renal perfusion pressure (RPP) into the renal microvasculature, causing RPP-induced renal injury in CKD, little is known regarding the molecular mechanism mediating RPP-induced injury. Our preliminary data showed that silencing of HIF-1? attenuated renal injury without effect on hypertension in a rat 5/6 renal ablation/infarction model (5/6 A/I); maintaining a normal RPP blocked the increase of renal HIF-1? and suppressed the renal injury in this CKD model, indicating that HIF-1? may mediate RPP-induced renal injury. HIF prolyl- hydroxylases (prolyl hydroxylase domain-containing proteins, PHDs) are the major enzymes to promote the degradation of HIF-1? and present in the kidneys to regulate renal HIF-1?. We recently showed that PHDs play a critical role in TGF-?- and ANG II-induced activation of HIF-1? and consequent injuries in renal cells. Our preliminary data showed that renal PHD activity was inhibited by elevated RPP and that activating PHD activity attenuated renal injury in 5/6 A/I rats. Thus, PHD-mediated regulation of HIF-1? could be an important mechanism mediating RPP-induced injury. Further, the PHD activity is inhibited by the activation of TRPC6, a member of the Transient Receptor Potential Channels. The activation of TRPC6 is known to produce renal injury. Moreover, TRPC6 participates in the mechanical/pressure sensation in various cell types, including podocytes. Therefore, TRPC6 may be the upstream mediator that transmits the RPP stress into downstream molecular pathways to cause RPP-induced injury. Our preliminary data showed that the levels of renal TRPC6 was increased, which was inhibited by servo-control to block the increase of RPP in rats with 5/6 A/I. In addition, TRPC6 shRNA blocked the increase of HIF-1? in the kidneys of 5/6 A/I rats. The above information leads to a hypothesis that the elevated RPP activates TRPC6, which inhibits PHD activity to induce HIF-1?- mediated profibrogenic genes, consequently causing renal injuries in CKD. Three specific aims are proposed. Aim 1: To test the hypothesis that over-activation of HIF-1? mediates RPP-induced chronic renal injury in CKD. Aim 2: To test the hypothesis that elevated RPP inhibits PHD activity to up-regulate HIF-1?, thereby producing chronic renal injury in CKD. Aim 3: To test the hypothesis that TRPC6 is the upstream regulator sensing pressure stress to regulate PHD/HIF-1? pathway in RPP-induced renal injury in CKD. The results from these proposed studies will define an important molecular mechanism associated with TRPC6/PHD/HIF-1? pathway in RPP-induced injury in CKD, which will ultimately suggest new therapeutic targets for CKD.